The proportion of Alzheimer's disease attributable to apolipoprotein E

Abstract

Objective To estimate the proportions of Alzheimer's disease (AD) and all-cause dementia burden attributable to the common risk alleles {varepsilon}3 and {varepsilon}4 in the APOE gene Design Genetic association analyses in three independent cohort studies and one case-control study Settings National cohorts in the UK and Finland (UK Biobank, FinnGen); a pre-intervention cohort of participants in the A4 Study, a multi-national randomised clinical trial; AD case-control samples from the Alzheimer's Disease Genomics Consortium (ADGC) in the U.S. Participants Cohorts aged [≥]60 years in UK Biobank (n=171,128) and FinnGen (n=279,036). Cognitively normal trial recruits with baseline neuroimaging aged 65 to 85 years in A4 (n=4,415). Deceased AD cases and controls in ADGC (mean age ~ 82 years; n=5,007) Main outcomes Clinically diagnosed AD and all-cause dementia, principally or exclusively ascertained through health record linkages (UK Biobank, FinnGen); Cerebral amyloidosis ascertained through Positron Emission Tomography neuroimaging (A4); AD neuropathologically confirmed at autopsy (ADGC). Results In UKB, 73.9% (95% confidence interval: 37.3% to 89.0%) of AD and 37.8% (9.1% to 57.4%) of all-cause dementia were attributable to a combination of {varepsilon}3 and {varepsilon}4 carriage. In FinnGen, estimates were 64.4% (45.1% to 76.6%) for AD and 42.4% (25.0% to 55.4%) for all-cause dementia. In the A4 study, 85.1% (19.2% to 93.9%) of cerebral amyloidosis was attributable to {varepsilon}3 and {varepsilon}4. In the ADGC data, 92.7% (81.4% to 96.5%) of neuropathologically confirmed AD was attributable to {varepsilon}3 and {varepsilon}4, with {varepsilon}4 accounting for 56.9% (36.0% to 63.0%) and {varepsilon}3 for 35.8% (22.1% to 58.3%). Conclusions Without the strong risk-increasing effects of both APOE {varepsilon}3 and {varepsilon}4, most AD would not occur. Apolipoprotein E (apoE) predominates late-onset AD's causes. Research into apoE should be prioritised given its major potential as a target for AD prevention and treatment.